CC BY ND NC 4.0 · SynOpen 2018; 02(02): 0150-0160
DOI: 10.1055/s-0036-1591960
paper
Copyright with the author

Synthesis of Substituted Pyrido-oxazine through Tandem SN2 and SNAr Reaction

Mosim Amin Pathan
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana, 502 285, India   Email: faiz@iith.ac.in
,
Faiz Ahmed Khan*
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana, 502 285, India   Email: faiz@iith.ac.in
› Author Affiliations
F.A.K. gratefully acknowledges DBT for financial support. M.A.P. thanks CSIR for the award of a fellowship
Further Information

Publication History

Received: 15 January 2018

Accepted: 23 February 2018

Publication Date:
16 May 2018 (online)

 

Abstract

Pyrido-oxazine derivatives have been synthesized by employing tandem SN2 and SNAr reaction between 2,4,6-tribromo-3-(2-bromoethoxy)pyridine or 2,4,6-tribromo-3-(3-bromopropoxy)pyridine and a variety of primary amines. Moderate to good regioselectivity in favor of cyclization at the 2-position is observed. Pyrido-oxazine products thus generated are converted into biarylated pyrido-oxazine and terpyridine ligands.


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Pyridine is an important heterocycle that is frequently encountered in natural products, bioactive molecules, and therapeutic drugs and serves also as a common synthetic building block.[1] There is a demand for reactions that allow direct functionalization of pyridine. Phenanthroline, bipyridine, terpyridine (Figure [1]) and their derivatives have been extensively used as organic ligands with a variety of metals to perform important synthetic transformations.[2] Pyrido-oxazines are a class of heterocycles in which one of the carbon atoms in benzoxazine is replaced with nitrogen, and such compounds have shown promising biological activity.[3] Halo-pyridines are important building blocks in organic synthesis because they easily react with various nucleo­philes. This reactive nature can be attributed to the high electronegativity of the halogen atom, which makes carbon–halogen bonds prone to nucleophilic aromatic substitutions (SNAr). In general, substituted 2- and 4-halopyridines are attractive intermediates in synthetic and medicinal chemistry and they are extensively used for the construction of various pyridine-based heterocycles including N-fused heterocycles.[4] This electrophilic character of halopyridines has also been used in pyrido-oxazines syntheses.[5] Several other synthetic protocols are also available in the literature.[6] However there is a need to develop alternative methods in view of the importance of these scaffolds. In a continuation of our ongoing program of synthesizing brominated marine natural product and their analogues,[7] we wish to report a simple strategy for the synthesis of functionalized pyrido-oxazines by employing a tandem SN2 and SNAr reaction.

We have recently reported a synthesis of dihydrobenzoxazines and tetrahydrobenzoxazepines by employing complementary ambiphile pairing (CAP) and complementary pairing (CP) method through an interesting N-dealkylative SNAr substitution reaction with activated aromatic halides.[8] We thought of extending the same protocol for the synthesis of pyrido-oxazines. Unlike our previous work,[8] the pyridine moiety does not require an EWG activating group and therefore 2,4,6-tribromopyridin-3-ol (1) and 3-chloro-N,N-dimethylpropan-1-amino hydrochloride (1ab) appeared to be a suitable substrate pair for this study.

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Figure 1 The important pyridine motif

Accordingly, when 1 was treated with 1ab, we observed the formation of regioisomeric seven-membered N-demethylative products 1a and 1b in 44% overall yield. Similarly, treatment of 1 with 2-chloro-N,N-dimethylethanamino hydrochloride (2ab) gave 2a and 2b in 54% overall yield (Scheme [1]).

Zoom Image
Scheme 1 N-Dealkylative cyclization

Alternatively, transformation of 1 into 6a and 6b would furnish bis-electrophilic species, which, upon treatment with primary amines, would provide the corresponding products, without a N-demethylative pathway.[8] Phenol 1, on treatment with 1,2-dibromoethane, gave bis-electrophile 6a in 54% yield, and similar treatment of 1,3-dibromopropane gave 6b in 85% yield (Scheme [2]). When 6a was subjected to aqueous methylamine (2ba) in DMF at ambient temperature, cyclized products 2a and 2b were obtained in 80% overall yield (Scheme [3]). To check the scope of the reaction, 6a was then subjected to a variety of primary amines. This methodology tolerates functional groups including allyl (2c, 2d), cyclopropyl (2g, 2h), and benzyl (2o, 2p) (Scheme [3]). Interestingly the use of a chiral amine afforded the cyclic products 2k, 2l in good yield. 2-(Aminomethyl)aniline 2qr, which has two free NH2 groups, reacted selectively at the benzyl amino group to give the products 2q and 2r in good yield. Biologically important indole derivatives 2u and 2v were prepared in good yield. This methodology has also been used to prepare seven-membered pyrido-oxazine derivatives 1ad in good yield.

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Scheme 2 Synthesis of bis-electrophilic intermediates 6a and 6b
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Scheme 3 Cyclization with primary amines

The structural assignment of the two regioisomeric (2- or 4-cyclized) products was based on the characteristic 13C NMR values of methine carbon shifts in the pyridine ring of the two isomers. As depicted in Figure [2], for the 2-cyclized isomer the methine carbon appears in the range δ = 119.6–117.6 ppm and the signal for the 4-cyclized isomer resonates between δ = 110.4–108.1 ppm. An unambiguous confirmation was obtained by single- crystal X-ray analysis of 2p (Figure [2]). A similar difference, δ = 119.8–121.5 ppm for 2-cyclized isomer and δ = 112.4–114.3 ppm for 4-cyclized isomer, allowed assignment of the seven-membered derivatives.

Zoom Image
Figure 2 Characteristic 13C NMR shifts of the 2- and 4-isomer and single-crystal X-ray structure of compound 2p (CCDC 1584958)

With pyrido-oxazine products in hand, we thought of utilizing bromine atoms at the 2,6- or 4,6-positions for further functionalization through standard procedures. Application of Suzuki–Miyaura reaction furnished biarylated pyrido-oxazine 7ag in good yield (Scheme [4]). Similarly, Stille coupling between pyrido-oxazine 2b and 2-(tributylstannyl)pyridine 8 in the presence of Pd(PPh3)4 gave terpyridine ligand 8a in good yield (Scheme [5]). This reaction was then extended to 1a, 2l, 2k, 2c, 2g to obtain terpyridine ligands 8bf in good yield.

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Scheme 4 Synthesis of biarylated pyrido-oxazine
Zoom Image
Scheme 5 Synthesis of terpyridine ligand

In conclusion, we have developed a method for the synthesis of pyrido-oxazine through tandem SN2 and SNAr reaction in good yield. We were also able to functionalize pyrido-oxazine to form biarylated pyrido-oxazine and terpyridines using Suzuki and Stille coupling reactions in moderate to good yield.

All starting material and reagents were purchased from standard commercial sources or were prepared in the laboratory. All the glassware were cleaned with soap water followed by acetone and dried in a hot air oven at 100 °C for 2 h. Solvents were distilled prior to use. IR spectra were recorded with a Bruker Tensor 37 (FTIR) spectrophotometer.1H NMR spectra were recorded with a Bruker Avance 400 (400 MHz) spectrometer at 295 K in CDCl3; chemical shifts (δ, ppm) and coupling constants (Hz) are reported with reference to either tetramethylsilane (TMS) (δ = 0.00 ppm ppm) or CHCl3 (δ = 7.26 ppm). 13C NMR spectra were recorded with a Bruker Avance 400 (100 MHz) spectrometer at 298 K in CDCl3; chemical shifts (δ, ppm) are reported relative to CHCl3 (δ = 77.00 ppm; central line of triplet). For 13C NMR analysis, the nature of the carbon atoms (C, CH, CH2, and CH3) was determined by recording DEPT-135 spectra. In 1H NMR data, the following abbreviations are used throughout: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, and br. s = broad singlet. The assignment of the signals was confirmed by 1H, 13C and DEPT spectra. High-resolution mass spectra (HRMS) were recorded with an Agilent 6538 UHD Q-TOF using multimode source in +ESI method at the Department of Chemistry, Indian Institute of Technology Hyderabad, India. Reactions were monitored by TLC on silica gel (254 mesh) using a combination of hexane and EtOAc as eluents.


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2,4,6-Tribromopyridin-3-ol (1)

To a solution of 3-hydroxypyridine (5 g, 52.5 mmol) in H2O (60 mL) was added bromine (10.84 mL, 210 mmol) at 0 °C and the reaction mixture was stirred at r.t. for 12 h. The formed solid was filtered through suction filter. Solid product 1 was collected and used without further purification.

Yield: 12 g (69%); yellow solid; mp 74–76 °C; Rf = 0.5 (60%, EtOAc/hexane).

IR (neat): 3743, 3677, 3617, 1698, 1540, 1516, 1459 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.60 (s, 1 H), 6.02 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 147.4, 131.1, 129.7, 128.6, 120.8.

HRMS (ESI+): m/z [M]+ calcd for C5H2Br3NO: 330.7666; found: 330.775.


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Typical Procedure and Spectral Data for 1a, 1b, 2a, 2b Obtained through N-Dealkylative Cyclization

To a stirred suspension of K2CO3 (167 mg, 1.208 mmol) in DMF (1 mL) was added 2,4,6-tribromopyridin-3-ol (1; 100 mg, 0.302 mmol) and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (1ab; 86 mg, 0.604 mmol) and, after stirring for 10 h at 120 °C, water (3 mL) was added. The mixture was extracted with EtOAc (8 × 3 mL) and the organic layer was washed with water (3 mL) and brine (3 mL), dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified over silica gel chromatography (20%, EtOAc­/hexane) to give 1a (38 mg, 39%) and 1b (5 mg, 5%) as colorless solids.


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7,9-Dibromo-5-methyl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (1a)

Yield: 38 mg (39%); white solid; mp 92–94 °C; Rf = 0.5 (10%, EtOAc­/hexane).

IR (neat): 2922, 1562, 1522, 1416, 1363, 1192, 1042, 962, 759 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.91 (s, 1 H), 4.24 (t, J = 6.4 Hz, 2 H), 3.56–3.48 (m, 2 H), 3.06 (s, 3 H), 2.19–2.04 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 154.3, 140.5, 131.4, 125.1, 119.8, 70.3, 50.0, 39.5, 28.0.

HRMS (ESI+): m/z [M + H]+ calcd for C9H11Br2N2O: 322.9218; found: 322.9201.


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6,8-Dibromo-1-methyl-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepine (1b)

Yield: 5 mg (5%); white solid; mp 98–100 °C; Rf = 0.5 (10%, EtOAc/hexane).

1H NMR (400 MHz, CDCl3): δ = 6.57 (s, 1 H), 4.31–4.22 (m, 2 H), 3.62–3.53 (m, 2 H), 2.99–2.90 (m, 3 H), 2.21–2.09 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 151.7, 141.2, 134.0, 133.9, 112.5, 70.2, 51.9, 40.8, 28.0.

IR (neat): 2925, 1564, 1511, 1426, 1382, 1264, 1196, 1040 cm–1.

HRMS (ESI+): m/z [M + H]+ calcd for C9H11Br2N2O: 322.9218; found: 322.9202.


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6,8-Dibromo-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2a)

Yield: 38 mg (41%); white solid; mp 82–84 °C; Rf = 0.5 (10%, EtOAc­/hexane).

IR (neat): 2939, 2892, 1580, 1531, 1510, 1451, 1415, 1357, 1302, 1211, 1051, 922, 778, 695 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 1 H), 4.3 (t, J = 4.4 Hz, 2 H), 3.48 (t, J = 4.4 Hz, 2 H), 3.11 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.8, 136.4, 129.7, 118.6, 117.9, 64.4, 47.7, 36.2.

HRMS (ESI+): m/z [M + H]+ calcd for C8H9Br2N2O: 308.9061; found: 308.9053.


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5,7-Dibromo-1-methyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2b)

Yield: 12 mg (36%); white solid; mp 138–140 °C; Rf = 0.2 (10%, EtOAc­/hexane).

IR (neat): 2945, 2882, 1581, 1509, 1461, 1426, 1352, 1290, 1249, 1217, 1119, 1052, 926, 822, 790 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.56 (s, 1 H), 4.31 (t, J = 4.4 Hz, 2 H), 3.43 (t, J =4.4 Hz, 2 H), 2.97 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 144.0, 136.8, 131.6, 126.9, 108.5, 64.1, 48.0, 37.9.

HRMS (ESI+): m/z [M + H]+ calcd for C17H16Br2N3O: 308.9061; found: 308.9053.


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2,4,6-Tribromo-3-(2-bromoethoxy)pyridine (6a)

To a stirred suspension of K2CO3 (4.99 g, 36.15 mmol) in DMF (35 mL) was added 2,4,6-tribromopyridin-3-ol (1; 4 g, 12.05 mmol) and the mixture was stirred at 0 °C for 0.5 h. 1,2-Dibromoethane (11.32 g, 60.25 mmol) was added and, after stirring for 12 h at 80 °C, water (100 mL) was added. The mixture was extracted with EtOAc (80 × 2 mL) and the organic layer was washed with water (12 × 3 mL) and brine (20 × 2 mL), dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified over silica gel chromatography (10%, EtOAc/hexane) to give 2,4,6-tribromo-3-(2-bromoethoxy)pyridine 6a.

Yield: 2.45 g, 46%); colorless solid; mp 60–62 °C; Rf = 0.5 (10%, EtOAc­/hexane).

IR (neat): 2924, 1516, 1412, 1310, 985, 742 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.66 (s, 1 H), 4.35 (t, J = 6.5 Hz, 2 H), 3.72 (t, J = 6.5 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 150.2, 136.7, 134.8, 131.5, 129.7, 72.9, 28.6.

HRMS (ESI+): m/z [M + H]+ calcd for C7H6Br4NO: 439.7142; found: 439.7134.


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2,4,6-Tribromo-3-(3-bromopropoxy)pyridine (6b)

To a stirred suspension of K2CO3 (2.5 g, 18.12 mmol) in DMF (20 mL) was added 2,4,6-tribromopyridin-3-ol (1; 2 g, 6.02 mmol) and the mixture was stirred at 0 °C for 0.5 h. 1,3-Dibromopropane (6.08 g, 30.1 mmol) was added and after stirring for 4 h at 80 °C, water (40 mL) was added. The mixture was extracted with EtOAc (30 × 2 mL) and the organic layer was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified over silica gel chromatography (20%, EtOAc/hexane) to give 2,4,6-tribromo-3-(3-bromopropoxy)pyridine 6b.

Yield: 1.67 g (61%); colorless solid; mp 40–42 °C; Rf = 0.7 (20%, EtOAc­/hexane).

IR (neat): 2950, 1517, 1416, 1311, 996, 742 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.65 (s, 1 H), 4.18 (t, J = 5.6 Hz, 2 H), 3.70 (t, J = 6.4 Hz, 2 H), 2.41 (quin, J = 6.4, 5.7 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 150.5, 136.9, 134.4, 131.5, 129.8, 71.4, 33.17, 29.5.

HRMS (ESI+): m/z [M]+ calcd for C8H7Br4NO: 452.7220; found: 452.7368.


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Typical Procedure and Spectral Data for 2c–x

To a solution of 2,4,6-tribromo-3-(2-bromoethoxy)pyridine (6a; 100 mg, 0.228 mmol) in DMF (1 mL) was added benzyl amine (73 mg, 0.684 mmol) and the reaction mixture was stirred at r.t. for 36 h. Water (3 mL) was then added and the mixture was extracted with EtOAc (12 × 3 mL). The combined organic phases were washed with water (3 mL), brine (3 mL), dried over Na2SO4 and concentrated in vacuo The resulting crude residue was purified over silica gel column chromatography (10–20%, EtOAc/hexane) to afford product 2o (52 mg, 59%) and 2p (26 mg, 30%).


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4-Allyl-6,8-dibromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2c)

Yield: 45 mg (59%); white solid; mp 54–56 °C; Rf = 0.6 (10%, EtOAc­/hexane).

IR (neat); 3093, 2939, 1578, 1534, 1502, 1449, 1418, 1357, 1305, 1255, 1213, 1094, 1040, 992, 925, 806, 673 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.85 (s, 1 H), 5.89–5.72 (m, 1 H), 5.27–5.16 (m, 2 H), 4.27 (t, J = 4.4 Hz, 2 H), 4.21 (d, J = 5.9 Hz, 2 H), 3.44 (t, J = 4.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 145.8, 135.1, 131.7, 128.5, 117.6, 117.2, 117.1, 63.4, 49.1, 43.5.

HRMS (ESI+): m/z [M + H]+ calcd for C10H11Br2N2O: 334.9218; found: 334.9212.


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1-Allyl-5,7-dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2d)

Yield: 26 mg (34%); white solid; mp 78–80 °C; Rf = 0.2 (10%, EtOAc­/hexane).

IR (neat): 3086, 2874, 1576, 1528, 1503, 1454, 1402, 1352, 1287, 1246, 1211, 1167, 1070, 1035, 925, 822, 796, 700, 662 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.58 (s, 1 H), 5.78 (tdd, J = 5.0, 10.4, 17.2 Hz, 1 H), 5.33–5.11 (m, 2 H), 4.3 (t, J = 4.4 Hz, 2 H), 3.91 (td, J = 1.7, 5.0 Hz, 2 H), 3.46 (t, J = 4.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 143.1, 136.7, 131.7, 130.2, 127.5, 118.1, 108.7, 64.0, 52.8, 46.3.

HRMS (ESI+): m/z [M + H]+ calcd for C10H11Br2N2O: 334.9218; found: 334.9212.


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6,8-Dibromo-4-ethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2e)

Yield: 42 mg (57%); white solid; mp 82–84 °C; Rf = 0.6 (10%, EtOAc/hexane).

IR (neat): 2932, 1578, 15051443, 1358, 1209, 1058, 930, 767 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.82 (s, 1 H), 4.31–4.23 (m, 2 H), 3.64 (q, J = 7.2 Hz, 2 H), 3.53–3.44 (m, 2 H), 1.17 (t, J = 7.1 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.9, 136.1, 129.7, 118.0, 117.9, 64.3, 44.7, 42.7, 11.7.

HRMS (ESI+): m/z [M + H]+ calcd for C9H11Br2N2O: 322.9218; found: 322.9209.


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5,7-Dibromo-1-ethyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2f)

Yield: 22 mg (30%); white solid; mp 78–80 °C; Rf = 0.2 (10%, EtOAc/hexane).

IR (neat): 2932, 1578, 1505, 1423, 1358, 1209, 1058, 930, 767 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.59 (s, 1 H), 4.32–4.24 (m, 2 H), 3.46–3.42 (m, 2 H), 3.36 (q, J = 7.3 Hz, 2 H), 1.27–1.12 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 142.8, 136.8, 131.7, 127.4, 108.1, 63.9, 45.5, 45.0, 10.9.

HRMS (ESI+): m/z [M + H]+ calcd for C9H11Br2N2O: 322.9218; found: 322.9209.


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6,8-Dibromo-4-cyclopropyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2g)

Yield: 30 mg (39%); white solid; mp 91–93 °C; Rf = 0.5 (10%, EtOAc­/hexane).

IR (neat): 2979, 1575, 1485, 1443, 1354, 1219, 1118, 1023 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.93 (s, 1 H), 4.31–4.23 (m, 2 H), 3.51–3.43 (m, 2 H), 2.68 (tt, J = 3.5, 7.0 Hz, 1 H), 0.93–0.82 (m, 2 H), 0.68–0.58 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 148.0, 136.6, 129.5, 119.6, 117.9, 65.3, 45.7, 30.5, 7.6.

HRMS (ESI+): m/z [M + H]+ calcd for C10H11Br2N2O: 334.9218; found: 334.9214.


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5,7-Dibromo-1-cyclopropyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2h)

Yield: 33 mg (43%); white solid; mp 142–144 °C; Rf = 0.2 (10%, EtOAc­/hexane).

IR (neat): 2958, 1574, 1487, 1451, 1348, 1251, 1116, 1026, 823 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.05 (s, 1 H), 4.28 (br. s., 2 H), 3.42 (br. s., 2 H), 2.48 (br. s., 1 H), 0.99–0.88 (m, 2 H), 0.69 (br. s., 2 H).

13C NMR (100 MHz, CDCl3): δ = 144.4, 137.2, 131.1, 127.1, 110.4, 64.9, 45.7, 31.1, 8.1.

HRMS (ESI+): m/z [M + H]+ calcd for C10H11Br2N2O: 334.9218; found: 334.9211.


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6,8-Dibromo-4-propyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2i)

Yield: 41 mg (54%); gummy solid; Rf = 0.5 (10%, EtOAc/hexane).

IR (neat): 2927, 1578, 1504, 1423, 1357, 1300, 1211, 1061, 938, 746.

1H NMR (400 MHz, CDCl3): δ = 6.81 (s, 1 H), 4.29–4.22 (m, 2 H), 3.59–3.43 (m, 4 H), 1.70–1.55 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.1, 135.8, 131.5, 129.6, 117.9, 64.3, 49.6, 45.5, 20.1, 11.4.

HRMS (ESI+): m/z [M + H]+ calcd for C10H13Br2N2O: 336.9374; found: 336.9365.


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5,7-Dibromo-1-propyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2j)

Yield: 24 mg (31%); white solid; mp 67–69 °C; Rf = 0.2 (10%, EtOAc/hexane).

IR (neat): 2933, 1505, 1403, 1065, 939, 797 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.57 (s, 1 H), 4.32–4.23 (m, 2 H), 3.49–3.42 (m, 2 H), 3.28–3.19 (m, 2 H), 1.65 (sext, J = 7.4 Hz, 2 H), 0.97 (t, J = 7.3 Hz, 3 H).

13C NMR (100 MHz, 400 MHz, CDCl3): δ = 143.1, 136.6, 131.7, 127.4, 108.1, 63.8, 52.3, 46.5, 19.5, 11.4.

HRMS (ESI+): m/z [M + H]+ calcd for C10H13Br2N2O: 336.9374; found: 336.9383.


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(S)-6,8-Dibromo-4-(1-phenylethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2k)

Yield: 47 mg (52%); gummy solid; Rf = 0.2 (10%, EtOAc/hexane).

IR (neat): 2938, 1574, 1488, 1415, 1353, 1211, 1064, 775, 699 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.37–7.23 (m, 5 H), 6.87 (s, 1 H), 6.20 (q, J = 7.0 Hz, 1 H), 4.25–4.16 (m, 1 H), 4.03 (ddd, J = 2.9, 7.5, 10.6 Hz, 1 H), 3.32 (ddd, J = 3.2, 7.5, 12.8 Hz, 1 H), 3.04 (ddd, J = 2.7, 4.5, 12.8 Hz, 1 H), 1.61–1.50 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.7, 140.2, 136.0, 131.5, 129.5, 128.5, 127.5, 127.4, 118.3, 72.9, 64.6, 51.0, 39.3, 28.6, 15.1.

HRMS (ESI+): m/z [M + H]+ calcd for C15H15Br2N2O: 398.9531; found: 398.9521.


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(S)-5,7-Dibromo-1-(1-phenylethyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2l)

Yield: 24 mg (26%); white solid; mp 106–108 °C; Rf = 0.3 (10%, EtOAc/hexane).

IR (neat): 2938, 1574, 1488, 1415, 1353, 1211, 1064, 775, 699 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.44–7.21 (m, 5 H), 6.80 (s, 1 H), 5.08 (q, J = 6.8 Hz, 1 H), 4.31–4.21 (m, 1 H), 4.09 (ddd, J = 2.9, 7.7, 10.9 Hz, 1 H), 3.30 (ddd, J = 3.2, 7.5, 12.8 Hz, 1 H), 3.17–3.04 (m, 1 H), 1.68–1.52 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 143.2, 139.0, 136.8, 131.8, 129.0, 128.1, 127.9, 126.8, 108.5, 64.2, 55.0, 40.1, 15.8.

HRMS (ESI+): m/z [M + H]+ calcd for C15H15Br2N2O: 398.9531; found: 398.952.


#

4-Benzyl-6,8-dibromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2o)

Yield: 52 mg (59%); gummy solid; Rf = 0.3 (10%, EtOAc/hexane).

IR (neat): 2836, 2899, 1576, 1533, 1500, 1445, 1417, 1356, 1298, 1210, 1048, 915, 737, 697 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.34–7.25 (m, 5 H), 6.88 (s, 1 H), 4.80 (s, 2 H), 4.21 (t, J = 4.4 Hz, 2 H), 3.37 (t, J = 4.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 147.0, 136.9, 136.0, 129.5, 128.7, 128.2, 127.6, 118.8, 118.5, 64.4, 50.9, 44.5.

HRMS (ESI+): m/z [M + H]+ calcd for C14H13Br2N2O: 384.9374; found: 384.9364.


#

1-Benzyl-5,7-dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2p)

Yield: 26 mg (30%); white solid; mp 142–144 °C; Rf = 0.2 (10%, EtOAc­/hexane).

IR (neat): 2931, 2874, 1574, 1528, 1501, 1453, 1352, 1246, 1072, 922, 799, 733, 697 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.45–7.29 (m, 3 H), 7.24–7.14 (m, 2 H), 6.65 (s, 1 H), 4.51 (s, 2 H), 4.31 (t, J = 4.4 Hz, 2 H), 3.48 (t, J = 4.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 143.4, 136.7, 135.0, 131.8, 129.2, 128.1, 127.7, 126.8, 108.7, 64.1, 53.9, 46.5.

HRMS (ESI+): m/z [M + H]+ calcd for C14H13Br2N2O: 384.9374; found: 384.9365.


#

2-((6,8-Dibromo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl)aniline (2q)

Yield: 48 mg (53%); white solid; mp 81–83 °C; Rf = 0.7 (10%, EtOAc­/hexane).

1H NMR (400 MHz, CDCl3): δ = 7.18–7.04 (m, 2 H), 6.87 (s, 1 H), 6.74–6.63 (m, 2 H), 4.68 (s, 2 H), 4.55 (br. s., 2 H), 4.21 (t, J = 4.4 Hz, 2 H), 3.45 (t, J = 4.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 146.9, 146.2, 136.2, 131.5, 129.4, 129.2, 119.8, 118.7, 118.6, 117.4, 115.9, 64.3, 49.0, 44.5.

IR (neat): 3450, 3339, 3220, 3010, 2895, 1631, 1575, 1502, 1443, 1354, 1298, 1251, 1206, 1162, 1111, 1041, 908, 747 cm–1.

HRMS (ESI+): m/z [M + H]+ calcd for C14H14Br2N3O: 399.9483; found: 399.9473.


#

2-((5,7-Dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)methyl)aniline (2r)

Yield: 23 mg (25%); white solid; mp 164–166 °C; Rf = 0.2 (10%, EtOAc­/hexane).

IR (neat): 3743, 2929, 1572, 1504, 1456, 1401, 1354, 1247 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.19 (dt, J = 1.2, 7.7 Hz, 1 H), 7.01 (d, J = 7.3 Hz, 1 H), 6.82–6.72 (m, 3 H), 4.34 (s, 2 H), 4.3 (t, J = 4.4 Hz, 2 H), 3.71 (br. s., 2 H), 3.29 (t, J = 4.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 144.8, 143.6, 137.2, 131.7, 129.5, 129.1, 127.7, 119.0, 118.3, 116.4, 109.0, 64.5, 50.9, 44.5.

HRMS (ESI+): m/z [M + H]+ calcd for C14H14Br2N3O: 399.9483; found: 399.9476.


#

tert-Butyl 3-(6,8-Dibromo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)propylcarbamate (2s)

Yield: 40 mg (39%); gummy solid; Rf = 0.3 (25%, EtOAc/hexane).

IR (neat): 3743, 3616, 3346, 2929, 1698, 1577, 1518, 1360, 1167, 1067 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.83 (s, 1 H), 5.56 (br. s., 1 H), 4.25 (t, J = 4.4 Hz, 2 H), 3.64 (t, J = 6.4 Hz, 2 H), 3.48 (t, J = 4.4 Hz, 2 H), 3.10 (q, J = 6.4 Hz, 2 H), 1.74 (quin, J = 6.1 Hz, 2 H), 1.48–1.40 (m, 9 H).

13C NMR (100 MHz, CDCl3): δ = 156.2, 147.3, 135.9, 129.5, 118.4, 78.9, 64.2, 45.5, 45.0, 36.0, 28.5, 27.4.

HRMS (ESI+): m/z [M + Na]+ calcd for C15H21Br2N3NaO3: 473.9827; found: 473.9779.


#

tert-Butyl 3-(5,7-Dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)propylcarbamate (2t)

Yield: 27 mg (26%); white solid; mp 121–123 °C; Rf = 0.2 (25%, EtOAc­/hexane).

IR (neat): 3343, 2773, 2933, 1694, 1577, 1520, 1459, 1401, 1359, 1281, 1248, 1167, 1065, 930, 796 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.55 (s, 1 H), 4.70 (br. s, 1 H), 4.27 (t, J = 4.4 Hz, 2 H), 3.45 (t, J = 4.4 Hz, 2 H), 3.33 (t, J = 7.3 Hz, 2 H), 3.22–3.15 (m, 2 H), 1.80 (quin, J = 7.0 Hz, 2 H), 1.48–1.37 (m, 9 H).

13C NMR (100 MHz, CDCl3): δ = 156.1, 142.9, 136.8, 131.6, 127.5, 108.1, 79.7, 63.9, 48.1, 46.5, 38.0, 28.4 (3×CH3), 27.0.

HRMS (ESI+): m/z [M + H]+ calcd for C15H22Br2N3O3: 452.0007; found: 451.9996.


#

4-(2-(1H-Indol-3-yl)ethyl)-6,8-dibromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2u)

Yield: 57 mg (57%); white solid; mp 62–64 °C; Rf = 0.3 (25%, EtOAc­/hexane).

IR (neat): 3413, 2932, 1577, 1532, 1504, 1450, 1421, 1357, 1258, 1210, 1088, 1041, 927, 742 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.85 (br. s, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.24 (d, J = 7.8 Hz, 1 H), 7.16–7.03 (m, 2 H), 6.88 (d, J = 2.0 Hz, 1 H), 6.77 (s, 1 H), 4.02–3.93 (m, 2 H), 3.75 (t, J = 7.3 Hz, 2 H), 3.27–3.19 (m, 2 H), 2.97 (t, J = 7.8 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 146.8, 136.3, 136.0, 129.9, 127.5, 122.2, 122.0, 119.5, 119.2, 118.1, 117.9, 113.3, 111.2, 64.3, 49.3, 46.3, 22.9.

HRMS (ESI+): m/z [M + H]+ calcd for C17H16Br2N3O: 437.9640; found: 437.9628.


#

1-(3-(1H-Indol-3-yl)propyl)-5,7-dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2v)

Yield: 30 mg (30%); gummy solid; Rf = 0.1 (25%, EtOAc/hexane).

IR (neat): 3400, 1658, 1578, 1523, 1355, 1247, 1021, 999, 822, 759, 620 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 10.85 (br. s, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.08 (dt, J = 1.2, 7.5 Hz, 1 H), 7.02–6.94 (m, 1 H), 6.74 (s, 1 H), 4.11 (t, J = 4.4 Hz, 2 H), 3.64 (t, J = 7.1 Hz, 2 H), 3.37–3.32 (m, 2 H), 2.96 (t, J = 7.1 Hz, 2 H).

13C NMR (100 MHz, DMSO-d 6): δ = 143.3, 136.2, 136.1, 130.8, 127.0, 126.1, 123.3, 121.0, 118.4, 118.0, 111.5, 110.8, 107.8, 63.5, 50.4, 45.8, 21.4.

HRMS (ESI+): m/z [M + H]+ calcd for C17H16Br2N3O: 437.9640; found: 437.9631.


#

6,8-Dibromo-4-butyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2w)

Yield: 47 mg (59%); gummy solid; Rf = 0.4 (10%, EtOAc/hexane).

IR (neat): 2925, 1694, 1513, 1460, 1211 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.81 (s, 1 H), 4.26 (t, J = 4.4 Hz, 2 H), 3.58 (t, J = 7.1 Hz, 2 H), 3.49 (t, J = 4.4 Hz, 2 H), 1.58 (quin, J = 7.1, 15 Hz, 2 H), 1.35 (qd, J = 7.2, 15.0 Hz, 2 H), 0.96 (t, J = 7.3 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.1, 135.9, 131.5, 129.7, 117.9, 64.3, 47.6, 45.4, 29.0, 20.1, 13.9.

HRMS (ESI+): m/z [M + H]+ calcd for C11H15Br2N2O: 350.9531; found: 350.9516.


#

5,7-Dibromo-1-butyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2x)

Yield: 24 mg (30%); white solid; mp 47–49 °C; Rf = 0.2 (10%, EtOAc­/hexane).

IR (neat): 2956, 2868, 1577, 1505, 1459, 1403, 1354, 1246, 1210, 1066, 920, 818, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.56 (s, 1 H), 4.26 (t, J = 4.4 Hz, 2 H), 3.44 (t, J = 4.4 Hz, 2 H), 3.27 (t, J = 7.8 Hz, 2 H), 1.59 (quin, J = 7.3 Hz, 2 H), 1.45–1.29 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 143.1, 136.6, 131.7, 127.4, 108.1, 63.8, 50.5, 46.5, 28.2, 20.2, 13.9.

HRMS (ESI+): m/z [M + H]+ calcd for C11H15Br2N2O: 350.9531; found: 350.952.


#

7,9-Dibromo-5-cyclopropyl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (1c)

Yield: 25 mg (33%); white solid; mp 60–62 °C; Rf = 0.6 (10%, EtOAc­/hexane).

IR (neat): 1559, 1526, 1467, 1434, 1370, 1349, 1308, 1278, 1203, 1094, 1061, 1023, 949, 878, 820, 777, 689 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.05 (s, 1 H), 4.16 (t, J = 6.1 Hz, 2 H), 3.61–3.52 (m, 2 H), 2.80 (tt, J = 3.5, 7.0 Hz, 1 H), 2.01 (quin, J = 6.0 Hz, 2 H), 0.87–0.76 (m, 2 H), 0.57–0.48 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 155.1, 141.3, 131.2, 125.1, 121.5, 70.3, 50.2, 33.8, 29.5, 8.3.

HRMS (ESI+): m/z [M + H]+ calcd for C11H13Br2N2O: 348.9374; found: 348.9365.


#

6,8-Dibromo-1-cyclopropyl-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepine (1d)

Yield: 23 mg (36%); white solid; mp 106–108 °C; Rf = 0.2 (10%, EtOAc­/hexane).

IR (neat): 3086, 2956, 1562, 1518, 1444, 1385, 1336, 1281, 1234, 1062, 1025, 990, 951, 836, 689 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.01 (s, 1 H), 4.18 (t, J = 5.8 Hz, 2 H), 3.64 (t, J = 5.8 Hz, 2 H), 2.55 (tt, J = 3.3, 6.7 Hz, 1 H), 2.05 (quin, J = 6.0 Hz, 2 H), 0.94–0.83 (m, 2 H), 0.67–0.58 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 152.1, 141.5, 133.7, 133.2, 114.3, 70.2, 51.4, 34.0, 29.5, 9.0.

HRMS (ESI+): m/z [M + H]+ calcd for C11H13Br2N2O: 348.9374; found: 348.9366.


#

Typical Procedure and Spectral Data for 7a–g

To solution of 5,7-dibromo-1-methyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2b; 40 mg, 0.129 mmol) in dioxane (1 mL) was added Pd(PPh3)4 (14 mg, 0.0129 mmol), o-tolylboronic acid and aq 2 M K2CO (0.2 mL). The reaction mixture was stirred for 8 h at 80 °C. Water (4 mL) was added and the mixture was extracted with EtOAc (12 × 3 mL). The combined organic phases were washed with brine (3 mL), dried over Na2SO4 and concentrated in vacuo. The resulting crude material was purified over silica gel column chromatography (10%, EtOAc­/hexane) to afford product 7g (32 mg, 74%).


#

4-Benzyl-6,8-diphenyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (7a)

Synthesized from 2o (11 mg).

Yield: 9 mg (82%); white solid; mp 144–146 °C; Rf = 0.5 (10%, EtOAc­/hexane).

IR (neat): 1693, 1648, 1515, 1462, 756 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.05–7.97 (m, 2 H), 7.63 (dd, J = 1.2, 8.6 Hz, 2 H), 7.51–7.23 (m, 11 H), 7.12 (s, 1 H), 5.07 (s, 2 H), 4.26–4.18 (m, 2 H), 3.51–3.42 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 146.9, 146.8, 139.7, 138.6, 135.6, 135.0, 129.2, 128.6, 128.4, 128.2, 127.9, 127.7, 127.2, 126.2, 111.1, 64.3, 51.0, 45.1.

HRMS (ESI+): m/z [M + H]+ calcd for C26H23N2O: 379.1810; found: 379.1796.


#

1-Methyl-5,7-diphenyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (7b)

Yield: 23 mg (59%); white solid; mp 130–132 °C; Rf = 0.4 (10%, EtOAc­/hexane).

IR (neat): 2930, 1589, 1507, 1235, 774, 696 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 7.8 Hz, 4 H), 7.42 (t, J = 7.3 Hz, 4 H), 7.34 (d, J = 4.4 Hz, 2 H), 6.91 (s, 1 H), 4.26 (br. s, 2 H), 3.41 (br. s, 2 H), 3.02 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 150.4, 144.1, 142.9, 140.5, 138.4, 129.6, 128.5, 128.0, 128.0, 127.9, 126.8, 102.4, 64.0, 48.5, 38.2.

HRMS (ESI+): m/z [M + H]+ calcd for C20H19N2O: 303.1497; found: 303.149.


#

4-Benzyl-6,8-di(naphthalen-1-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (7c)

Synthesized from 2o (62 mg).

Yield: 52 mg (68%); white solid; mp 170–172 °C; Rf = 0.7 (10%, EtOAc­/hexane).

IR (neat): 3051, 1546, 1454, 1358, 1046, 778 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.46 (d, J = 8.8 Hz, 1 H), 7.93–7.74 (m, 5 H), 7.69–7.61 (m, 1 H), 7.58–7.21 (m, 12 H), 6.95–6.87 (m, 1 H), 5.10–5.00 (m, 1 H), 4.97–4.85 (m, 1 H), 4.16–4.03 (m, 2 H), 3.50–3.33 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 148.9, 146.7, 138.9, 138.5, 135.9, 134.9, 134.2, 134.1, 133.6, 131.5, 131.4, 128.6, 128.4, 128.4, 128.3, 128.2, 127.3, 127.2, 126.7, 126.3, 126.2, 125.9, 125.9, 125.6, 125.4, 125.4, 117.4, 64.2, 51.0, 45.4.

HRMS (ESI+): m/z [M + H]+ calcd for C34H27N2O: 479.2123; found: 479.213.


#

5-Methyl-7,9-diphenyl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (7d)

Synthesized from 1a (50 mg).

Yield: 47 mg (96%); white solid; mp 89–91 °C; Rf = 0.7 (10%, EtOAc­/hexane).

IR (neat): 2950, 1544, 1497, 1370, 1202, 1036, 952, 762, 696 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.07–8.00 (m, 2 H), 7.58–7.53 (m, 2 H), 7.49–7.33 (m, 6 H), 7.17 (s, 1 H), 4.20 (t, J = 6.1 Hz, 2 H), 3.60–3.49 (m, 2 H), 3.31–3.19 (m, 3 H), 2.18–2.06 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 154.4, 148.1, 141.2, 140.6, 139.5, 137.5, 129.2, 128.5, 128.1, 128.0, 127.9, 127.7, 126.4, 126.3, 112.6, 70.3, 50.6, 40.0, 29.1.

HRMS (ESI+): m/z [M + H]+ calcd for C21H21N2O: 317.1654; found: 317.1635.


#

(S)-6,8-Diphenyl-4-(1-phenylethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (7e)

Synthesized from 2k (70 mg).

Yield: 63 mg (91%); white solid; mp 116–118 °C; Rf = 0.5 (15%, EtOAc­/hexane).

IR (neat): 2932, 1594, 1484, 1440, 1358, 1207, 1029, 771, 744, 695 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.95–7.90 (m, 2 H), 7.55–7.50 (m, 2 H), 7.38–7.13 (m, 11 H), 7.00 (s, 1 H), 6.56 (q, J = 6.8 Hz, 1 H), 4.11–4.04 (m, 1 H), 3.95 (ddd, J = 2.9, 7.6, 10.5 Hz, 1 H), 3.30 (ddd, J = 2.9, 7.7, 12.3 Hz, 1 H), 3.03–2.97 (m, 1 H), 1.54 (d, J = 7.3 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.7, 146.5, 141.8, 139.8, 136.9, 135.6, 134.9, 129.2, 128.4, 128.4, 128.2, 127.8, 127.7, 127.5, 127.0, 126.2, 110.7, 64.4, 50.4, 39.5, 15.0.

HRMS (ESI+): m/z [M + H]+ calcd for C27H25N2O: 393.1967; found: 393.1956.


#

1-Cyclopropyl-5,7-diphenyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (7f)

Synthesized from 2h (35 mg).

Yield: 16 mg (47%); white solid; mp 55–57 °C; Rf = 0.4 (15%, EtOAc­/hexane).

IR (neat): 2929, 1583, 1546, 1505, 1358, 1231, 1023, 1023, 776 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.07–7.96 (m, 4 H), 7.50–7.41 (m, 5 H), 7.39–7.32 (m, 2 H), 4.38–4.19 (m, 2 H), 3.53–3.38 (m, 2 H), 2.60–2.45 (m, 1 H), 1.03–0.89 (m, 2 H), 0.83–0.66 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 150.0, 144.3, 143.0, 140.5, 138.4, 137.8, 129.6, 128.5, 127.9, 127.9, 127.8, 126.7, 115.3, 104.0, 64.8, 46.1, 31.3, 8.1.

HRMS (ESI+): m/z [M + H]+ calcd for C22H21N2O: 329.1654; found: 329.1647.


#

4-Methyl-6,8-di-o-tolyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (7g)

Yield: 32 mg (74%); white solid; mp 44–46 °C; Rf = 0.8 (10%, EtOAc­/hexane).

IR (neat): 2926, 1601, 1454, 1359, 1206, 1036, 759 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.51–7.43 (m, 1 H), 7.29–7.18 (m, 7 H), 6.55 (s, 1 H), 4.27–4.20 (m, 2 H), 3.50–3.42 (m, 2 H), 3.18 (s, 3 H), 2.50 (s, 3 H), 2.25 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 149.4, 147.1, 140.7, 136.7, 136.3, 136.1, 135.5, 134.6, 130.8, 129.9, 129.7, 129.5, 127.9, 127.4, 125.7, 125.6, 115.5, 64.2, 48.2, 36.3, 21.1, 20.1.

HRMS (ESI+): m/z [M + H]+ calcd for C22H23N2O: 331.1810; found: 331.1802.


#

Typical Procedure and Spectral Data for 8a–f

To a solution of (S)-5,7-dibromo-1-(1-phenylethyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2l; 85 mg, 0.213 mmol) in toluene (2 mL) was added Pd(PPh3)4 (24 mg, 0.0213 mmol), 2-(tributylstannyl)pyridine 8 and, after degassing under argon, the reaction mixture was stirred for 16 h at reflux. After completion of reaction, which was checked by TLC, the reaction mixture was filtered through a short pad of Celite and concentrated in vacuo. The resulting crude material was purified over 5% KF + silica gel column chromatography with 10% MeOH in CH2Cl2, which afforded product 8c (52 mg, 61%).


#

1-Methyl-5,7-di(pyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (8a)

Synthesized from 2b (60 mg).

Yield: 55 mg (92%); white solid; mp 102–104 °C; Rf = 0.2 (80%, EtOAc­/hexane).

IR (neat): 2934, 1560, 1501, 1433, 1364, 1203, 1050, 791, 607 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.76–8.68 (m, 1 H), 8.63–8.56 (m, 1 H), 8.35–8.28 (m, 1 H), 8.11 (s, 1 H), 7.82–7.78 (m, 1 H), 7.71 (dtd, J = 2.0, 7.7, 11.4 Hz, 2 H), 7.24–7.14 (m, 2 H), 4.33–4.26 (m, 2 H), 3.55–3.46 (m, 2 H), 3.25 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 156.7, 154.7, 149.5, 148.9, 147.6, 145.8, 138.1, 136.4, 135.8, 133.1, 124.9, 122.4, 122.3, 120.2, 112.0, 64.4, 47.8, 36.3.

HRMS (ESI+): m/z [M + H]+ calcd for C18H17N4O: 305.1402; found: 305.1391.


#

5-Methyl-7,9-di(pyridin-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (8b)

Synthesized from 1b (48 mg).

Yield: 46 mg (92%); white solid; mp 98–100 °C; Rf = 0.2 (25%, EtOAc­/hexane).

1H NMR (400 MHz, CDCl3): δ = 8.72 (td, J = 1.3, 4.8 Hz, 1 H), 8.64–8.57 (m, 1 H), 8.37–8.29 (m, 1 H), 8.11 (s, 1 H), 7.78–7.68 (m, 3 H), 7.28–7.16 (m, 2 H), 4.22 (t, J = 6.1 Hz, 2 H), 3.55 (dd, J = 5.1, 6.6 Hz, 2 H), 3.23 (s, 3 H), 2.15–2.08 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 156.6, 155.4, 154.3, 149.4, 148.9, 147.3, 142.9, 139.4, 136.5, 135.8, 125.0, 122.6, 122.4, 120.5, 113.4, 70.3, 50.5, 40.0, 28.8.

IR (neat): 2951, 1699, 1547, 1488, 1428, 1371, 1263, 1198, 1043, 792 cm–1.

HRMS (ESI+): m/z [M + H]+ calcd for C19H19N4O: 319.1559; found: 319.1547.


#

(S)-1-(1-Phenylethyl)-5,7-di(pyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (8c)

Yield: 52 mg (61%); white solid; mp 100–102 °C; Rf = 0.2 (5%, MeOH/CH2Cl2).

IR (neat): 1693, 1648, 1515, 1462, 754 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.79–8.73 (m, 1 H), 8.62–8.58 (m, 1 H), 8.47 (d, J = 8.3 Hz, 1 H), 8.07 (d, J = 1.0 Hz, 1 H), 7.93–7.89 (m, 1 H), 7.82–7.70 (m, 2 H), 7.41–7.32 (m, 4 H), 7.31–7.25 (m, 2 H), 7.21 (ddd, J = 1.0, 4.9, 7.3 Hz, 1 H), 5.57 (q, J = 6.8 Hz, 1 H), 4.25–4.17 (m, 1 H), 4.08 (ddd, J = 2.9, 7.5, 10.6 Hz, 1 H), 3.36 (ddd, J = 2.9, 7.6, 12.5 Hz, 1 H), 3.14–3.03 (m, 1 H), 1.66 (d, J = 6.8 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 157.3, 156.7, 149.3, 148.9, 148.6, 144.1, 142.2, 140.1, 139.4, 136.6, 136.0, 128.7, 127.6, 127.2, 124.9, 122.8, 122.5, 121.2, 103.1, 64.2, 54.0, 39.8, 15.2;

HRMS (ESI+): m/z [M + H]+ calcd for C25H23N4O: 395.1872; found: 395.1867.


#

(S)-4-(1-Phenylethyl)-6,8-di(pyridin-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (8d)

Yield: 78 mg (91%); white solid; mp 118–120 °C; Rf = 0.2 (30%, EtOAc­/hexane).

IR (neat): 2931, 1698, 1300, 1254, 1174, 1060, 789 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.75–8.71 (m, 1 H), 8.60 (td, J = 1.0, 4.9 Hz, 1 H), 8.31 (d, J = 8.3 Hz, 1 H), 8.11 (s, 1 H), 7.82–7.77 (m, 1 H), 7.71 (tt, J = 1.8, 7.8 Hz, 2 H), 7.46–7.41 (m, 2 H), 7.37–7.30 (m, 2 H), 7.28–7.20 (m, 2 H), 7.17 (ddd, J = 1.0, 4.9, 7.3 Hz, 1 H), 6.61 (q, J = 6.8 Hz, 1 H), 4.25–4.17 (m, 1 H), 4.09 (ddd, J = 2.9, 7.5, 10.6 Hz, 1 H), 3.42 (ddd, J = 3.2, 7.3, 12.5 Hz, 1 H), 3.15–3.08 (m, 1 H), 1.63 (d, J = 7.3 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 156.8, 154.9, 149.5, 148.9, 146.4, 145.7, 141.6, 137.7, 136.5, 135.9, 133.7, 128.5, 127.4, 127.1, 124.9, 122.5, 122.4, 120.3, 111.7, 64.6, 50.7, 39.3, 15.0.

HRMS (ESI+): m/z [M + H]+ calcd for C25H23N4O: 395.1872; found: 395.1865.


#

4-Benzyl-6,8-di(pyridin-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (8e)

Synthesized from 2o (96 mg).

Yield: 63 mg (67%); white solid; mp 150–152 °C; Rf = 0.2 (35%, EtOAc­/hexane).

IR (neat): 2928, 1560, 1497, 1436, 1362, 1204, 1043, 747 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.77–8.69 (m, 1 H), 8.63–8.56 (m, 1 H), 8.30–8.23 (m, 1 H), 8.14 (s, 1 H), 7.83–7.78 (m, 1 H), 7.69 (dtd, J = 2.0, 7.8, 11.7 Hz, 2 H), 7.40–7.35 (m, 2 H), 7.34–7.29 (m, 2 H), 7.28–7.20 (m, 2 H), 7.15 (ddd, J = 1.0, 4.8, 7.5 Hz, 1 H), 5.04 (s, 2 H), 4.31–4.17 (m, 2 H), 3.52–3.38 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 156.7, 154.8, 149.5, 148.9, 146.8, 145.8, 138.4, 137.7, 136.5, 135.9, 133.8, 128.6, 128.1, 127.2, 124.9, 122.5, 122.4, 120.3, 112.1, 64.4, 51.2, 45.0;

HRMS (ESI+): m/z [M + H]+ calcd for C24H21N4O: 381.1715; found: 381.1703.


#

4-Cyclopropyl-6,8-di(pyridin-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (8f)

Synthesized from 2g (50 mg).

Yield: 44 mg (89%); white solid; mp 118–120 °C; Rf = 0.3 (40%, EtOAc­/hexane).

IR (neat): 2951, 1517, 1416, 1375, 1311, 1247, 997, 742 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.75–8.71 (m, 1 H), 8.60 (td, J = 1.2, 5.0 Hz, 1 H), 8.43–8.38 (m, 1 H), 8.18 (s, 1 H), 7.82–7.68 (m, 3 H), 7.25–7.14 (m, 2 H), 4.37–4.19 (m, 2 H), 3.60–3.43 (m, 2 H), 2.80–2.63 (m, 1 H), 1.03–0.87 (m, 2 H), 0.78–0.65 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 156.9, 154.8, 149.5, 148.8, 147.9, 145.7, 138.3, 136.5, 135.8, 133.3, 124.9, 122.4, 122.3, 120.3, 112.9, 65.4, 46.0, 31.0, 7.8.

HRMS (ESI+): m/z [M + H]+ calcd for C20H19N4O: 331.1559; found: 331.1546.


#
#

Supporting Information

  • References

    • 1a Francisco W. Pivatto M. Danuello A. Regasini LO. Baccini LR. Young MC. M. Lopes NP. Lopes JL. C. Bolzani VS. J. Nat. Prod. 2012; 75: 408
    • 1b Fu P. Zhu Y. Mei X. Wang Y. Jia H. Zhang C. Zhu W. Org. Lett. 2014; 16: 4264
    • 1c Fu P. Liu P. Li X. Wang Y. Wang S. Hong K. Zhu W. Org. Lett. 2011; 13: 5948
    • 1d Qu X. Pang B. Zhang Z. Chen M. Wu Z. Zhao Q. Zhang Q. Wang Y. Liu Y. Wen L. J. Am. Chem. Soc. 2012; 134: 9038
    • 2a Kitanosono T. Zhu L. Liu C. Xu P. Kobayashi S. J. Am. Chem. Soc. 2015; 137: 15422
    • 2b Kawakami T. Murakami K. Itami K. J. Am. Chem. Soc. 2015; 137: 2460
    • 2c Jensen KL. Standley EA. Jamison TF. J. Am. Chem. Soc. 2014; 136: 11145
    • 2d Wendlandt AE. Stahl SS. J. Am. Chem. Soc. 2014; 136: 506
    • 2e Petersen AR. Taylor RA. Vicente-Hernández I. Mallender PR. Olley H. White AJ. P. Britovsek GJ. P. J. Am. Chem. Soc. 2014; 136: 14089
    • 3a Watterson SH. Chen P. Zhao Y. Gu HH. Dhar TG. M. Xiao Z. Ballentine SK. Shen Z. Fleener CA. Rouleau KA. Obermeier M. Yang Z. McIntyre KW. Shuster DJ. Witmer M. Dambach D. Chao S. Mathur A. Chen B.-C. Barrish JC. Robl JA. Townsend R. Iwanowicz EJ. J. Med. Chem. 2007; 50: 3730
    • 3b Wu W.-L. Burnett DA. Domalski M. Greenlee WJ. Li C. Bertorelli R. Fredduzzi S. Lozza G. Veltri A. Reggiani A. J. Med. Chem. 2007; 50: 5550
    • 3c Perry B. Alexander R. Bennett G. Buckley G. Ceska T. Crabbe T. Dale V. Gowers L. Horsley H. James L. Jenkins K. Crépy K. Kulisa C. Lightfoot H. Lock C. Mack S. Morgan T. Nicolas A.-L. Pitt W. Sabin V. Wright S. Bioorg. Med. Chem. Lett. 2008; 18: 4700
    • 3d Hinman MM. Rosenberg TA. Balli D. Black-Schaefer C. Chovan LE. Kalvin D. Merta PJ. Nilius AM. Pratt SD. Soni NB. Wagenaar FL. Weitzberg M. Wagner R. Beutel BA. J. Med. Chem. 2006; 49: 4842
    • 4a Kazuhisa I. Toshiaki N. Mika M. Tomomi I. Tetrahedron 2015; 71: 407
    • 4b Taisuke K. Yoshihide T. Tetsuya T. Yoshihisa N. Tetrahedron Lett. 2015; 56: 6043
    • 4c Vadim B.-G. Arturo A. Antonio A. Mehdi B. Robert H. Alexey K. Pedro R.-N. Alexander T. Ralf S. ACS Chem. Neurosci. 2015; 6: 260
    • 4d Haoran S. Stephen GD. Angew. Chem. Int. Ed. 2006; 45: 2720
    • 4e Carla B. Thierry R. Manfred S. Chem. Eur. J. 2005; 11: 1903
    • 4f Mark P. Simon C. Edward M. Julian B. Tetrahedron 2010; 66: 2398
    • 4g Anita T. William RW. Robert FS. Bioorg. Med. Chem. 2002; 10: 3593
    • 4h Joydev KL. Gregory DC. Synthesis 2008; 4002
    • 5a Kim JG. Yang EH. Youn WS. Choi JW. Ha D.-C. Ha JD. Tetrahedron Lett. 2010; 51: 3886
    • 5b Brooks G. Dabbs S. Davies DT. Hennessy AJ. Jones GE. Markwell RE. Miles TJ. Owston NA. Pearson ND. Peng TW. Tetrahedron Lett. 2010; 51: 5035
    • 5c Isabelle T. Carsten B. Org. Lett. 2012; 14: 1892
    • 5d Graham S. Rachel S. Dmitrii SY. Judith AK. H. Antonio V. J. Fluorine Chem. 2014; 167: 91
    • 6a Sharifi A. Barazandeh M. Abaee MS. Mirzaei M. Tetrahedron Lett. 2010; 51: 1852
    • 6b Ramesh C. Raju BR. Kavala V. Kuo C.-W. Yao C.-F. Tetrahedron 2011; 67: 1187
    • 6c Dai W.-M. Wang X. Ma C. Tetrahedron 2005; 61: 6879
    • 6d Bower JF. Szeto P. Gallagher T. Org. Lett. 2007; 9: 3283
    • 6e Arrault A. Touzeau F. Guillaumet G. Léger J.-M. Jarry C. Mérour J.-Y. Tetrahedron 2002; 58: 8145
    • 6f Hartz RA. Nanda KK. Ingalls CL. Tetrahedron Lett. 2005; 46: 1683
    • 6g Henry N. Guillaumet G. Pujol MD. Tetrahedron Lett. 2004; 45: 1465
    • 7a Khan FA. Ahmad S. J. Org. Chem. 2012; 77: 2389
    • 7b Khan FA. Ahmad S. Tetrahedron Lett. 2013; 54: 2996
    • 7c Khan FA. Ahmad S. Kodipelli N. Shivange G. Anindya R. Org. Biomol. Chem. 2014; 12: 3847
  • 8 Pathan MA. Khan FA. Tetrahedron 2017; 6008

  • References

    • 1a Francisco W. Pivatto M. Danuello A. Regasini LO. Baccini LR. Young MC. M. Lopes NP. Lopes JL. C. Bolzani VS. J. Nat. Prod. 2012; 75: 408
    • 1b Fu P. Zhu Y. Mei X. Wang Y. Jia H. Zhang C. Zhu W. Org. Lett. 2014; 16: 4264
    • 1c Fu P. Liu P. Li X. Wang Y. Wang S. Hong K. Zhu W. Org. Lett. 2011; 13: 5948
    • 1d Qu X. Pang B. Zhang Z. Chen M. Wu Z. Zhao Q. Zhang Q. Wang Y. Liu Y. Wen L. J. Am. Chem. Soc. 2012; 134: 9038
    • 2a Kitanosono T. Zhu L. Liu C. Xu P. Kobayashi S. J. Am. Chem. Soc. 2015; 137: 15422
    • 2b Kawakami T. Murakami K. Itami K. J. Am. Chem. Soc. 2015; 137: 2460
    • 2c Jensen KL. Standley EA. Jamison TF. J. Am. Chem. Soc. 2014; 136: 11145
    • 2d Wendlandt AE. Stahl SS. J. Am. Chem. Soc. 2014; 136: 506
    • 2e Petersen AR. Taylor RA. Vicente-Hernández I. Mallender PR. Olley H. White AJ. P. Britovsek GJ. P. J. Am. Chem. Soc. 2014; 136: 14089
    • 3a Watterson SH. Chen P. Zhao Y. Gu HH. Dhar TG. M. Xiao Z. Ballentine SK. Shen Z. Fleener CA. Rouleau KA. Obermeier M. Yang Z. McIntyre KW. Shuster DJ. Witmer M. Dambach D. Chao S. Mathur A. Chen B.-C. Barrish JC. Robl JA. Townsend R. Iwanowicz EJ. J. Med. Chem. 2007; 50: 3730
    • 3b Wu W.-L. Burnett DA. Domalski M. Greenlee WJ. Li C. Bertorelli R. Fredduzzi S. Lozza G. Veltri A. Reggiani A. J. Med. Chem. 2007; 50: 5550
    • 3c Perry B. Alexander R. Bennett G. Buckley G. Ceska T. Crabbe T. Dale V. Gowers L. Horsley H. James L. Jenkins K. Crépy K. Kulisa C. Lightfoot H. Lock C. Mack S. Morgan T. Nicolas A.-L. Pitt W. Sabin V. Wright S. Bioorg. Med. Chem. Lett. 2008; 18: 4700
    • 3d Hinman MM. Rosenberg TA. Balli D. Black-Schaefer C. Chovan LE. Kalvin D. Merta PJ. Nilius AM. Pratt SD. Soni NB. Wagenaar FL. Weitzberg M. Wagner R. Beutel BA. J. Med. Chem. 2006; 49: 4842
    • 4a Kazuhisa I. Toshiaki N. Mika M. Tomomi I. Tetrahedron 2015; 71: 407
    • 4b Taisuke K. Yoshihide T. Tetsuya T. Yoshihisa N. Tetrahedron Lett. 2015; 56: 6043
    • 4c Vadim B.-G. Arturo A. Antonio A. Mehdi B. Robert H. Alexey K. Pedro R.-N. Alexander T. Ralf S. ACS Chem. Neurosci. 2015; 6: 260
    • 4d Haoran S. Stephen GD. Angew. Chem. Int. Ed. 2006; 45: 2720
    • 4e Carla B. Thierry R. Manfred S. Chem. Eur. J. 2005; 11: 1903
    • 4f Mark P. Simon C. Edward M. Julian B. Tetrahedron 2010; 66: 2398
    • 4g Anita T. William RW. Robert FS. Bioorg. Med. Chem. 2002; 10: 3593
    • 4h Joydev KL. Gregory DC. Synthesis 2008; 4002
    • 5a Kim JG. Yang EH. Youn WS. Choi JW. Ha D.-C. Ha JD. Tetrahedron Lett. 2010; 51: 3886
    • 5b Brooks G. Dabbs S. Davies DT. Hennessy AJ. Jones GE. Markwell RE. Miles TJ. Owston NA. Pearson ND. Peng TW. Tetrahedron Lett. 2010; 51: 5035
    • 5c Isabelle T. Carsten B. Org. Lett. 2012; 14: 1892
    • 5d Graham S. Rachel S. Dmitrii SY. Judith AK. H. Antonio V. J. Fluorine Chem. 2014; 167: 91
    • 6a Sharifi A. Barazandeh M. Abaee MS. Mirzaei M. Tetrahedron Lett. 2010; 51: 1852
    • 6b Ramesh C. Raju BR. Kavala V. Kuo C.-W. Yao C.-F. Tetrahedron 2011; 67: 1187
    • 6c Dai W.-M. Wang X. Ma C. Tetrahedron 2005; 61: 6879
    • 6d Bower JF. Szeto P. Gallagher T. Org. Lett. 2007; 9: 3283
    • 6e Arrault A. Touzeau F. Guillaumet G. Léger J.-M. Jarry C. Mérour J.-Y. Tetrahedron 2002; 58: 8145
    • 6f Hartz RA. Nanda KK. Ingalls CL. Tetrahedron Lett. 2005; 46: 1683
    • 6g Henry N. Guillaumet G. Pujol MD. Tetrahedron Lett. 2004; 45: 1465
    • 7a Khan FA. Ahmad S. J. Org. Chem. 2012; 77: 2389
    • 7b Khan FA. Ahmad S. Tetrahedron Lett. 2013; 54: 2996
    • 7c Khan FA. Ahmad S. Kodipelli N. Shivange G. Anindya R. Org. Biomol. Chem. 2014; 12: 3847
  • 8 Pathan MA. Khan FA. Tetrahedron 2017; 6008

Zoom Image
Figure 1 The important pyridine motif
Zoom Image
Scheme 1 N-Dealkylative cyclization
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Scheme 2 Synthesis of bis-electrophilic intermediates 6a and 6b
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Scheme 3 Cyclization with primary amines
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Figure 2 Characteristic 13C NMR shifts of the 2- and 4-isomer and single-crystal X-ray structure of compound 2p (CCDC 1584958)
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Scheme 4 Synthesis of biarylated pyrido-oxazine
Zoom Image
Scheme 5 Synthesis of terpyridine ligand